Elliot L. Servais

Outcome of Primary Tumor in Patients With Synchronous Stage IV Colorectal Cancer Receiving Combination Chemotherapy Without Surgery As Initial Treatment

CRA4030 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text].PURPOSE The purpose of this study was to describe the frequency of interventions necessary to palliate the intact primary tumor in patients who present with synchronous, stage IV colorectal cancer (CRC) and who receive up-front modern combination chemotherapy without prophylactic surgery. PATIENTS AND METHODS By using a prospective institutional database, we identified 233 consecutive patients from 2000 through 2006 with synchronous metastatic CRC and an unresected primary tumor who received oxaliplatin- or irinotecan-based, triple-drug chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin; bolus fluorouracil, leucovorin, and irinotecan; or fluorouracil, leucovorin, and irinotecan) with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumor complications was recorded. RESULTS Of 233 patients, 217 (93%) never required surgical palliation of their primary tumor. Sixteen patients (7%) required emergent surgery for primary tumor obstruction or perforation, 10 patients (4%) required nonoperative intervention (ie, stent or radiotherapy), and 213 (89%) never required any direct symptomatic management for their intact primary tumor. Of those 213 patients, 47 patients (20%) ultimately underwent elective colon resection at the time of metastasectomy, and eight patients (3%) underwent this resection during laparotomy for hepatic artery infusion pump placement. Use of bevacizumab, location of the primary tumor in the rectum, and metastatic disease burden were not associated with increased intervention rate. CONCLUSION Most patients with synchronous, stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their intact primary tumor. These data support the use of chemotherapy, without routine prophylactic resection, as the appropriate standard practice for patients with neither obstructed nor hemorrhaging primary colorectal tumors in the setting of metastatic disease.

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

Regional CAR T cell delivery provides superior protection compared to systemic administration. An Amazon Model for CAR T Cell Delivery The success of chimeric antigen receptor (CAR) T cells in treating otherwise untreatable hematological malignancies has been a flag-bearer for cancer immunotherapy. Yet, moving these therapies to solid tumors has been restricted by T cell infiltration and persistence. Now, Adusumilli et al. take a page from online sellers—setting up regional distribution centers to improve delivery. They found that mesothelin-targeted CAR T cells administered directly to the lung outpaced those administered systemically by both efficacy and persistence in an orthotopic model of lung cancer. What’s more, these effects weren’t restricted to lung, as tumors in extrathoracic sites were also eliminated. If these results hold in patients, regional delivery could improve both the efficacy and efficiency of solid tumor immunotherapy. Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell–mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through “regional distribution centers.” On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients

Purpose: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biologic function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases. Experimental Design: Human and murine MPM cells with MSLN forced expression and short hairpin RNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples. Results: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, colocalized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n = 139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n = 72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors. Conclusions: Our data provide evidence elucidating a biologic role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN expressing MPM. As regional invasion is the characteristic feature in MSLN expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target. Clin Cancer Res; 18(9); 2478–89. ©2012 AACR.

Palliation and Pleurodesis in Malignant Pleural Effusion: The Role for Tunneled Pleural Catheters

Introduction: Despite increasing use of tunneled pleural catheters (TPCs), their efficacy as a definitive procedure for achieving palliation or spontaneous pleurodesis (SP) in the management of malignant pleural effusion (MPE) remains unclear. In the largest TPC series to date, we evaluate the efficacy for palliation and review the rate and predictors of SP. Methods: Retrospective review of 418 TPCs (355 patients) over 2 years (September 2007–September 2009) was performed. Palliation was deemed successful when the patient did not require any other subsequent effusion-directed drainage procedure. SP was defined as satisfying the following criteria: (a) TPC removal without need for further effusion-directed intervention during the patients lifespan and (b) no evidence of effusion reaccumulation by clinical and radiographic evidence at 1-month postremoval follow-up. Results: After TPC placement, no subsequent effusion-directed procedure was required for 380 of 418 (91%). SP was achieved after only 26% of TPCs (110 of 418), in which the median time to catheter removal was 44 days. Neither demographics nor primary tumor type predicted SP. In patients selected for TPC placement in the operating room, SP occurred in 36% (39 of 107), with 45% in loculated MPE (13 of 29, p = 0.014). Complications occurred after 20 TPCs (4.8%), with none occurring after bedside placement. Conclusion: TPC placement is safe and provides durable palliation, most often obviating the need for subsequent procedures in MPE patients. TPC, however, remains suboptimal at achieving pleurodesis.

Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-free and Overall Survival in Early-Stage Lung Adenocarcinoma

Purpose: In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biologic and clinical relevance. Experimental Design: In a training and validation set of patients with early-stage (I–III) lung ADC (n = 1,209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models. Results: MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS [HR = 1.78; 95% confidence interval (CI), 1.26–2.50; P < 0.01] and RFS (HR = 1.67; 95% CI, 1.21–2.27; P < 0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P = 0.001). Conclusions: MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy. Clin Cancer Res; 20(4); 1020–8. ©2013 AACR.

POINT: Clinical stage IA non–small cell lung cancer determined by computed tomography and positron emission tomography is frequently not pathologic IA non–small cell lung cancer: The problem of understaging

OBJECTIVE There is an increase in interest in limited resection for clinical stage IA non-small cell lung cancer. The purpose of this study was to evaluate the accuracy of the diagnosis of clinical stage IA non-small cell lung cancer when determined by both computed tomography and positron emission tomography scans and to determine factors associated with understaging. METHODS A retrospective review of a prospectively maintained database of patients with non-small cell lung cancer was performed. Patients with clinical stage IA cancer determined by preoperative computed tomography and positron emission tomography scan were reviewed. The influence of the following factors was analyzed with regard to accuracy of clinical staging: tumor size, location, histology, and positron emission tomography positivity. RESULTS Of the 266 patients identified, cancer was correctly staged in 65%. Final pathologic stages also included IB (15%), IIA (2.6%), IIB (4.1%), IIIA (4.9%), IIIB (7.5%), and IV (.08%). Positive lymph nodes were found in 11.7% of patients. Pathologic T classification changed in 28.2% of patients. Cancer in patients with clinical tumor size greater than 2 cm (n = 68) was significantly more likely to be understaged than in patients with tumors 2 cm or less (49% vs 29%, P = .003). Cancer in patients with a positron emission tomography-positive (positron emission tomography +VE) primary evaluation (n = 218) was also more likely to be understaged (39% vs 15%, P = .001). Of patients with positron emission tomography +VE tumors greater than 2 cm, cancer was clinically understaged in 55%, compared with 32% for positron emission tomography +VE tumors 2 cm or less, and only 17% for positron emission tomography negative (-VE) tumors less than 2 cm. CONCLUSION Clinical stage IA lung cancer is frequently understaged in patients. Size greater than 2 cm and positron emission tomography positivity are risk factors for understaging. Limited resection should be undertaken with caution in such patients.

Tissue and Serum Mesothelin Are Potential Markers of Neoplastic Progression in Barrett's Associated Esophageal Adenocarcinoma

Background: Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barretts esophagus (BE) and in esophageal adenocarcinoma (EAC). Methods: Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum. Results: Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03–3.77 nmol/L), but not in patients with acid reflux and/or BE. Conclusions: Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483). Impact: Current surveillance methods in Barretts esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation. Cancer Epidemiol Biomarkers Prev; 21(3); 482–6. ©2012 AACR.

An In Vivo Platform for Tumor Biomarker Assessment

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.

Animal models and molecular imaging tools to investigate lymph node metastases

Lymph node metastasis is a strong predictor of poor outcome in cancer patients. Animal studies of lymph node metastasis are constrained by difficulties in the establishment of appropriate animal models, limitations in the noninvasive monitoring of lymph node metastasis progression, and challenges in the pathologic confirmation of lymph node metastases. In this comprehensive review, we summarize available preclinical animal cancer models for noninvasive imaging and identification of lymph node metastases of non-hematogenous cancers. Furthermore, we discuss the strengths and weaknesses of common noninvasive imaging modalities used to identify tumor-bearing lymph nodes and provide guidelines for their pathological confirmation.

Pre‐Clinical Mouse Models of Primary and Metastatic Pleural Cancers of the Lung and Breast and the Use of Bioluminescent Imaging to Monitor Pleural Tumor Burden

Malignant pleural disease (MPD) results in an estimated 150,000 cases of malignant pleural effusions (MPE) annually. The most common malignancies associated with MPD are primary malignant pleural mesothelioma (MPM) and metastatic lung cancer, breast cancer, and lymphoma. MPM is a rare, regionally aggressive malignancy whose incidence is increasing secondarily to the latency of disease progression. MPD is characteristic of advanced‐stage pleural disease and portends a grave clinical prognosis with a median survival between 3 and 12 months. Preclinical investigations conducted in flank and intraperitoneal tumor models do not fully recapitulate the pleural tumor microenvironment, and the results are not directly translatable to the clinical setting. The protocol described herein provides a mouse model of MPM and MPD from nonhematogenous tumors, resulting in reproducible tumor location, tumor progression, animal survival, and histopathology. Pleural tumor growth in this model resembles the regionally aggressive clinical course and tumor microenvironment of human pleural cancers and provides an optimal animal model to investigate MPD biology and therapies. Curr. Protoc. Pharmacol. 54:14.21.1‐14.21.18.